Process for manufacture of fosinopril sodium

ABSTRACT

The present invention discloses a process for the synthesis of fosinopril as a single desired isomer of high purity in two steps comprising of (a) preparation of fosinopril as a mixture of four diastereomers and (b) separation of the desired isomer from the mixture through formation of alkali metal salts followed by crystallisation.

This is a divisional of copending application Ser. No. 10/297,224 filedon Jun. 17, 2003 which is a 371 of PCT/IN01/00144 filed Aug. 17, 2001claims the benefit thereof and incorporates the same by reference.

The invention relates to an improved process for the synthesis of theangiotensin converting enzyme (ACE) inhibitor, fosinopril sodium offormula (I) in high purity.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 4,337,201 (Petrillo, Jr. et. al.) describes certain estersof phosphinylalkanoyl prolines or phosphinylalkanoyl substitutedprolines as inhibitors of angiotensin converting enzyme (ACE). Theseenzymes convert angiotensin I into angiotensin II, the latter being apowerful vasoconstrictor causing hypertension. Inhibition of ACE resultsin reduction of blood pressure, thereby improving the quality of life ofthe patient susceptible to or suffering from hypertension.

Among the phosphinylalkanoyl esters described in U.S. Pat. No. 4,337,201is the compound generically known as fosinopril sodium, marketed underthe brand name Monopril®. Fosinopril sodium is administrated orallyeither alone or in combination with diuretics for treatment ofhypertension. It is also used as an adjunct in the treatment ofcongestive heart failure.

Fosinopril is an optically active compound having total four centres ofasymmetry, three on carbon and one on phosphorous atom. Out of thesixteen isomers possible for this compound, only one of the isomers is atherapeutic i.e. a pharmaceutical. The desired isomer possessingtherapeutic value is[1[S*(R*)],2α,4β]-4-cyclohexyl-1-[[[2-methyl-1-(1-oxopropoxy)propoxy](4-phenylbutyl)phosphinyl]acetyl]-L-proline,mono-sodium salt and accordingly fosinopril sodium is represented byformula (I).

The prior art methods for synthesis of fosinopril, essentially consistsof the following:(i) Petrillo, Jr. et. al. in U.S. Pat. No. 4,337,201 discloses a processfor preparation of phosphinyl alkanoyl proline esters of general formula(3) comprising of reacting a phosphinyl acetic acid of formula (1) witha proline derivative of formula (2), the coupling reaction beingaccomplished using known amide forming procedures.

Alternatively, compound of formula (3) is prepared by alkylation of thehydroxy compound of formula (4) with a halo compound of formula (5),followed by basic hydrolysis.

In compounds of formula (1) to (5) mentioned hereinbefore synthesis offosinopril is achieved and completed when R¹ is phenylbutyl; R² isisobutylpropionate; R³ is hydrogen; R^(4a) is alkyl or arylalkyl,preferably benzyl; R⁴ is hydrogen; R⁵ is 4-cyclohexyl proline, n is zeroand X is halogen.

However, this patent does not:

(a) even remotely suggest any method for synthesising to specificallyobtain the desired isomer of fosinopril sodium (I), thus making it clearthat the product obtained by the methods described in the patent is amixture of either all possible sixteen isomers or is a mixture of someof the possible isomers,

(b) suggest, teach or disclose any method for separating the desiredisomer of fosinopril from the mixture of isomers and (c) suggest, teachor disclose any synthesis of esters of phosphinyl alkanoyl prolines withthe cycloalkyl group at the 4-position of the proline ring having a(trans) configuration. All examples described in the patent relate tosynthesis of such esters with the said cycloalkyl group having a (cis)configuration. The (trans) configuration of the cyclohexyl ring isrequired in fosinopril sodium.

(ii) Petrillo, Jr. et. al. in U.S. Pat. No. 4,873,356 describe a methodfor synthesis of the desired isomer of fosinopril sodium (I), which isan improvement over the general method described in U.S. Pat. No.4,337,201.

It addresses the shortcomings associated with the said U.S. Pat. No.4,337,201.

The method disclosed in this patent comprises of alkylating a phosphinylacetic acid derivative of formula (6) with a haloester of formula (7) inthe presence of an organic base selected from triethylamine, pyridine,tripropylamine and DBU to give the corresponding ester of formula (8) asa mixture of two diastereomers. The carboxylic acid ester protectivegroup is removed by hydrogenolysis to give the phosphinyl acetic acidcompound of formula (9), which is obtained as mixture of a pair ofracemic forms i.e. a mixture of two diastereomers, namely a mixture ofcompounds of formula (9A) and its mirror image (9B); (9C) and its mirrorimage (9D).

The racemic mixture of compounds (9A) and its mirror image (9B) isseparated from the other pair (9C) and its mirror image (9D) byrecrystallisation from suitable solvents such as isobutyl acetate ormethyl isobutyl ketone, which is further resolved by treatment withoptically active amines such as L-cinchonidine or other conventionalresolving agents to give the resolved salt of enantiomer (9B). Treatmentwith a strong acid gives the pure phosphinyl acetic acid isomer (9 B),the desired addendum for further elaboration to fosinopril sodium.

Thus, the pure single isomer (9 B) when reacted with(trans)-4-cyclohexyl-L-proline gives fosinopril, which is converted tothe sodium salt of formula (I) by conventional methods.

The chemistry practised in U.S. Pat. No. 4,873,356 is schematicallysummarised in Scheme-1

U.S. Pat. No. 4,873,356 further claims that compound (8) including allstereomers thereof, compound (9), including all stereomers thereof i.e.compound (9 A) and its mirror image (9 B); compound (9 C) and its mirrorimage (9 D) and the intermediate salt of compound (9 B) with theresolving agent are all novel compounds.

This further substantiates the earlier observation that separation ofsuch racemic mixtures or diastereomeric mixtures formed in the reactionwas never meant to be a part of the spirit and scope of the process(es)disclosed in U.S. Pat. No. 4,337,201.

(i) U.S. Pat. No. 5,008,399 (Sedergran et. al.) describes a processwhich is an improvement over that disclosed in U.S. Pat. No. 4,873,356.The improvement effected comprises carrying out the reaction of compound(6) and compound (7) in the presence of organic bases such as4-methylmorpholine, diazabicyclooctane, quinuclidine, 1-methylpyrolidineor cinchonidine to give compound (8) as a mixture of four isomers, whichon hydrogenolysis gives compound (9) as a mixture of two diastereomericpairs i.e. a mixture of compounds (9 A) and its mirror image (9 B); (9C) and its mirror image (9 D). The diastereomeric pair is separated andresolved as described in U.S. Pat. No. 4,873,356 to give the pure isomer(9 B).

U.S. Pat. No. 5,008,399 claims that by utilising the organic basesmentioned therein an increase in diastereoselectivity is achievedaffording the racemic mixture of compounds (9 A) and its mirror image (9B) in a ratio of 1.5 over the other racemic mixture i.e. (9 C) and itsmirror image (9 D). This is an improvement over a ratio of 1.2 achievedby employing a base such as triethylamine as disclosed in U.S. Pat. No.4,873,356. An overall increase in efficiency of preparing fosinoprilsodium (I) is thus achieved.

The processes described in U.S. Pat. Nos. 4,873,356 and 5,008,399, whileleading to the synthesis of fosinopril sodium having the desired opticalpurity, are associated with the following disadvantages. In particular,the processes of this patent:

-   -   involves separation of isomers that are mirror images of each        other i.e. enantiomers or a racemic mixture (9 A) and its mirror        image (9B) from (9 C) and its mirror image (9 D)    -   requires optical resolution for further separation of the        enantiomers (9 A).    -   requires optical resolution for further separation of the        enantiomers (9A) and its mirror image (9 B),    -   involves considerable wastage of the desired isomer (9 B) and        utilisation of expensive resolving agents (one to two molar        equivalents) and organic bases (about two molar equivalents), in        the separation of enantiomers followed by optical resolution        thereby resulting in an overall decrease in efficiency and        increase in the cost of manufacture of the end product i.e.        fosinopril sodium and    -   do not teach or disclose any method for recycling of the        unwanted isomers (9 A), (2) and (9D) back to the desired isomer        (9 B).        (i) Besides the aforementioned process patents, various methods        are reported for preparation of key intermediates required for        synthesis of fosinopril. For instance, U.S. Pat. No. 4,168,267        (Petrillo, Jr., et. al.), U.S. Pat. No. 4,384,123 (Petrillo.        Jr., et. al.), U.S. Pat. No. 4,448,772 (Karanewsky et. al.),        U.S. Pat. No. 4,594,199 (Thottathil et. al.) and U.S. Pat. No.        4,602,092 (Thottathil et. al.) disclose processes for synthesis        of the phosphinyl acetic acid fragment of fosinopril. U.S. Pat.        No. 4,316,905 (Krapcho et. al.), U.S. Pat. No. 4,501,901        (Thottathil et. al.), U.S. Pat. No. 4,588,819 (Thottathil et.        al.), U.S. Pat. No. 4,734,508 (Thottathil et. al.), U.S. Pat.        No. 4,912,230 (Anderson et. al.), U.S. Pat. No. 4,912,231        (Kronenthal et. al.) and U.S. Pat. No. 4,937,355 (Kloss et. al.)        describe processes for synthesis of the optically active        (cis/trans)-4-cyclohexyl-L-proline fragment.        (ii) In addition, it is known that the sodium salt of fosinopril        can exist in two polymorphic forms, designated as Form-A and        Form-B. The polymorphic forms differ in their respective solid        state IR, ¹³C NMR and ³¹P NMR spectra as well as X-ray (powder)        diffraction patterns. Of the two forms, Form-A, which is the        therapeutic is believed to be thermodynamically more stable. No        other polymorphic form for fosninopril sodium has been reported        so far.        (iii) U.S. Pat. No. 5,162,543 (Grosso et. al.) discloses a        selective process for preparation of any one of the two        polymorphs of fosinopril sodium as well as a process for inter        conversion of one form into the other. Polymorphic Form-A is        obtained by crystallisation of fosinopril sodium in a keto or        hydroxylic solvent or a mixture thereof in presence of water,        the requirement being water should constitute ≧2% or more of the        total solvent(s). When the crystallisation is carried out in a        keto or hydroxylic solvent or a mixture thereof, wherein the        water content is ≦0.2% Form-B is obtained. Rapid evaporation of        a methanolic solution of Form-A containing ≦0.2% of water        converts it to the other form i.e. Form-B.        (iv) The inference one draws from the methods described in U.S.        Pat. No. 5,162,543 is that the formation of the respective        polymorphs is not only dependent on the solvent employed but        also on the amount of water present in the solvents(s).

H. G. Brittain et. al. [Journal of Pharmaceutical & Biomedical Analysis,1993, Vol 11 (No. 11/12), pp 1063-1069] describe methods for preparationof the two polymorphic forms. For instance, Form-A is obtained bycrystallisation of fosinopril sodium from various organic solvents suchas acetone, acetonitrile, alcohols and the like containing water. Theauthors claim that formation of this polymorphic form is independent ofthe solvent used as long as the crystallisation is slow. There is nomention on the amount of water that is necessary for formation of thisform.

Form-B, on the other hand, is obtained by rapid/flash evaporation of thesolvent from a solution of fosinopril sodium in that solvent.

There are no reports available on the existence of polymorphic forms forother salts of fosinopril, such as alkali metal salts with lithium,potassium, rubidium and cesium or alkaline earth metal salts withberyllium, magnesium, calcium, strontium and barium or salts offosinopril with heavy metals.

Thus, to summarise the prior art:

a) the general methods described in U.S. Pat. No. 4,337,201 lead to amixture of all possible sixteen isomers or mixture of some of thepossible isomers of fosinopril. No method for separation and isolationof the pure desired isomer is mentioned,

b) the specific methods disclosed in U.S. Pat. Nos. 4,873,356 and5,008,399, lead to formation of only four isomers of fosinopril.However, enantiomers, which are mirror images of each other areseparated from the mixture,

c) separation of the pure desired isomer from the racemic mixture callsfor optical resolution,

d) optical resolution leads to considerable wastage of the desiredisomer leading to low efficiency and increase in cost of manufacture,

e) no method is described for recycling of the unwanted isomers back tothe desired one, and

f) formation of polymorphic Form-A of fosinopril sodium is dependent onthe solvent(s) employed and the amount of water present in thesolvent(s).

A need, therefore, exists for a method for the synthesis of fosinoprilsodium, which in addition to eliminating/minimising the disadvantages,specially optical resolution associated with the prior art methods,provides a cost-effective and convenient method for synthesis of theobjective compound.

SUMMARY OF THE INVENTION

Accordingly, in one aspect, the present invention provides a method forsynthesis of fosinopril as the desired single isomer comprisinga) reacting a phosphinyl acetic acid derivative of formula (IV)

wherein R⁷ is lower alkyl of 1-4 carbon atoms with(trans)-4-cyclohexyl-L-proline of structure (V) or a salt thereof, thecarboxylic acid group of which is activated by formation of its mixedanhydride, in presence of a base and an organic solvent

wherein R⁸ is a group easily removable by hydrogenolysis and is benzylor benzyl substituted at ortho, meta or para positions by an alkyl,alkoxy, alkanoyl, phenyl, nitro or dialkylamino groups to give thephosphinyl acetamido proline derivative of formula (VI), wherein R⁷ islower alkyl of 1-4 carbon atoms and removing the protective group R⁷ toobtain phosphinyl acetamido proline derivative of formula (VI), whereinR⁷ is hydrogen;

b) reacting a compound of formula (VI), wherein R7 is hydrogen with ahaloester of structure (VII),

wherein X is halogen in the presence of an organic base and a solvent togive the phosphinylalkanoyl proline ester of formula (II^(a))

c) removing the protective group R⁸ from the compound (II^(a)) thusobtained to give phosphinylalkanoyl proline ester i.e. fosinopril offormula (II) as a mixture of four diastereomers of formula (II A), (IIB), (II C) and (II D).

The chemistry utilised for synthesis of compound of formula (II) as amixture of four diastereomers (II A), (II B), (II C) and (II D) issummarised in Scheme-11.

In another aspect of the present invention there is provided a one-step,cost-effective method as summarised in Scheme-III for separation ofdiastereomer (II A) in high purity from the mixture of fourdiastereomers (II A), (II B), (II C) and (II D) comprisingd) mixing together the mixture of four diastereomers of formula (II A),(II B), (II C) and (II D) with a cesium salt in the presence of asolvent and crystallisation of the corresponding mixture of cesium saltsof compounds (II A), (II B), (II C) and (II D) from the same solvent ora mixture of solvents in the presence of 1 to 10 moles of water to givethe cesium salt of diastereomer (II A), isolated as the dihydrate offormula (III A) in high purity.

In yet another aspect of the present invention fosinopril cesium saltdihydrate of formula (III A) is provided, useful as an intermediate forsynthesis of fosinopril sodium of formula (I).

Yet another aspect of the present invention is to provide a convenientmethod for preparation of fosinopril sodium of formula (I),predominantly in the polymorphic Form-A as summarised in Scheme-IVcomprising

e) reacting fosinopril cesium salt dihydrate of formula (III A) with anacid to give the corresponding free acid compound,

f) mixing together the free carboxylic acid compound thus obtained witha sodium salt in the presence of organic solvent to give fosinoprilsodium of formula (I) and

g) slow crystallisation of fosinopril sodium thus obtained from asolvent containing water <0.2% over 10 to 24 hours to give fosinoprilsodium polymorph A.

In a further aspect of the present invention, a method is provided forrecycling of the undesired fosinopril diastereomers of structure (II B),(II C) and (II D) from the waste stream back to fosinopril sodium offormula (I), predominantly in the polymorphic Form-A comprisingh) subjecting the mixture of diastereomers of formula (II B), (II C) (IID) and (II A) or their alkali metal salts thereof contained in the wastestream mother liquor to hydrolysis to give a compound of formula (VIII)

i) selective esterification of the carboxylic acid of compound (VIII) togive compound of formula (VI), wherein R⁸ is a group easily removable byhydrogenolysis.

j) alkylation of compound (VI) by reaction with a haloester of formula(VII), wherein X is halogen

in the presence of an an acid or base and a solvent give compound(II^(a)) which on hydrogenolysis gives phosphinylalkanoyl proline esteri.e. fosinopril (II) as a mixture of four diastereomers of formula (IIA), (II B), (II C) and (II D) as described in sub-

j) conversion of compound mixture of four diastereomers of formula (IIA), (II B), (II C) and (II D) to the fosinopril cesium salt dihydrate offormula (III A) as described herein earlier in sub-section (d) andfinallyk) conversion of compound (III A) to fosinopril sodium polymorphicForm-A as described herein earlier in sub-sections (e) to (g).

The method for recycling of waste isomers back to the desiredtherapeutic isomer is summarised in Scheme-V.

To the best of our knowledge, synthesis of fosinopril sodium in highoptical and chemical purity employing the process describedhereinbefore, specially comprising of separation of diastereomers ratherthan separation of enantiomers has not been reported so far.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the IR spectrum of the (III A).

FIG. 3 shows the X-ray (powder) diffraction pattern of the compound (IIIA).

FIG. 3 shows the DSC of the compound (III A).

FIG. 4 shows the TG thermogram of the compound (III A).

DETAILED DESCRIPTION OF THE INVENTION

Fosinopril, viz. 1[{2-Methyl-1-(1-Oxopropoxy)propoxy)-4phenylbutyl}acetyl](trans)-4-cyclohexyl-L-Prolineof formula (II) has four centres of asymmetry in the molecule. Two suchcentres are present in the proline fragment of the compound i.e. at4-position of the proline ring to which the cyclohexyl group is attachedand at 2-position of the proline ring carrying the carboxylic acidfunction. The third centre is on the carbon atom number 12, which isattached to the phosphorous atom through oxygen linkage. The last one ison the phosphorous atom, which arises due to racemisation when theisobutylpropionate group is attached to it.

Because of the four asymmetric centres present in the molecule, compoundof formula (II) would give rise to sixteen isomers. Out of these, onlyone isomer is a therapeutic. As evident from prior art, the methodsdescribed in U.S. Pat. No. 4,337,201 probably lead to a synthesis offosinopril, probably obtained as a mixture of all possible sixteenisomers or as a mixture of some of the possible isomers.

Further, U.S. Pat. No. 4,337,201 neither suggests a method to separatethe desired isomer of therapeutic value from the mixture of otherunwanted isomers nor a method for synthesis of the product containingpredominantly the required isomer.

Thus, to summarise, practise of the chemistry embodied in U.S. Pat. No.4,337,201, comprising of reacting a compound of formula (4) with ahaloester of formula (5) to give compound of formula (3) wherein whenR¹, R², R³, R^(4a), R⁵, n and X are phenylbutyl, isobutylpropionate,hydrogen, alkyl or aralkyl, hydrogen, 4-cyclohexylproline, zero andhalogen respectively would give fosinopril of formula (II) as a mixtureof all possible sixteen isomers or as a mixture of some of the possibleisomers.

Separation of the isomers would be very tedious and if achieved, itwould not constitute a practical viable method for synthesis offosinopril

Synthesis of Fosinopril as a Single Desired Isomer of High Purity:

In the present invention this has been achieved in two steps i.e.

a) preparation of fosinopril as a mixture of four diastereomers and

b) separation of the desired isomer from the mixture through formationof alkali metal salts followed by crystallisation.

The process for preparation of fosinopril as a mixture of fourdiastereomers is accomplished as summarised in Scheme-II by

(i) Reacting a phosphinyl acetic acid derivative of formula (IV),wherein R⁷ is lower alkyl of 1-4 carbon atoms with(trans)-4-cyclohexyl-L-proline derivative of formula (V), in which thecarbon atoms at position no. 2 carrying the carboxylic acid group andposition no. 4 to which the cyclohexyl group is attached are both in the(S)-configuration and R⁸ is a group easily removable by hydrogenolysisand is preferably benzyl or benzyl substituted at ortho, meta or parapositions by an alkyl, alkoxy, alkanoyl, phenyl, nitro or a dialkylaminogroup, followed by removal of the protective group R⁷ by conventionalmeans to give the phosphinyl acetamido proline derivative of formula(VI), wherein R⁷ is hydrogen and R⁸ has the same meaning as mentionedhereinbefore

The reaction, which essentially involves formation of an amide bond, canbe accomplished in a number of ways as reported in the literature. Forexample, the reaction can be carried out by coupling of compound offormula (IV) and (V) in the presence of coupling agents such asdicyclohexylcarbodiimide or the compound of formula (IV) can be reactedwith compound of formula (V), after activation of the carboxylic acidfunction by formation of its mixed anhydride, symmetrical anhydride,acid halide and acid ester.

Preferably, in the present invention the amide bond formation isachieved by reacting compound of formula (IV) with compound of formula(V), the carboxylic acid function of which is activated by formation ofits mixed anhydride with pivaloyl chloride, in the presence of a baseand a solvent, to give compound of formula (VI), wherein R⁷ is loweralkyl of 1-4 carbon atoms.

The reaction can be carried out in a solvent selected from acetonitrile,dichloromethane, dichloroethane, dioxane, N,N-dimethylacetamide,N,N-dimethylformamide and tetrahydrofuran, or mixtures thereof. Anamount of solvent sufficient enough to dissolve the reactants isadequate.

Organic bases such as triethylamine, tripropylamine, pyridine, DBU andN-methyl morpholine can be used for the reaction. The bases can beemployed in a molar ratio to compound of formula (IV) of within therange from about 1:3, preferably from about 1:1.5 to about 1:2.

Normally, about one molar equivalent or a slight excess of the mixedanhydride with respect to compound (V) is sufficient for activation ofthe carboxylic acid function.

The reaction can be carried out at temperatures ranging from −60 to +30°C., preferably at a temperature ranging between −40 to 15° C.

In a preferred embodiment, a solution of compound (IV), wherein R⁷ ismethyl or ethyl in a solvent, preferably acetonitrile, dichloromethaneor tetrahydrofuran, and containing the organic base is reacted withpivaloyl chloride at a temperature ranging from −60 to −10° C. for about0.5 to 1.0 hours. To this solution is added a solution of(trans)-4-cyclohexyl-L-proline (V) in a solvent selected fromacetonitrile, dichloromethane or tetrahydrofuran at the same temperatureand allowed to react for 1 to 2 hrs at a temperature ranging from −40 to15° C. At the end of the reaction water is added to the reaction mixtureand the aqueous phase extracted with ethyl acetate. Evaporation of ethylacetate gives compound (VI), wherein R⁷ is lower alkyl of 1-4 carbonatoms.

(ii) Removal of the alkyl protective group R⁷ in compound of formula(VI) to give compound of formula (VI) in which the group R⁷ is hydrogen.This can be achieved by standard methods known in the art for hydrolysisof alkoxy esters. One such method consists of reacting compound offormula (VI) in which R⁷ is lower alkyl of 1-4 carbon atoms with a silylcompound or a mixture of silyl compounds optionally in the presence ofan alkali metal halide in presence of a solvent as per the methodsdescribed in Synthesis, 219 (1982) and Example 48 of U.S. Pat. No.4,337,201.

Preferably, the deprotection is carried out by reacting compound offormula (VI), in which R⁷ is lower alkyl of 1-4 carbon atoms with asilyl compound or a mixture selected from trimethyl chlorosilane,trimethylbromosilane and hexadimethylsilazane and in presence of analkali metal halide, such as sodium bromide and sodium iodide in anorganic solvent selected from acetonitrile, dichloromethane,dichloroethane, dioxane, N,N-dimethylacetamide, N,N-dimethylacetamide,tetrahydrofuran, toluene and xylene at a temperature ranging from 0 to110° C. for 1 to 2 hrs. At the end of the reaction, the hydroxy compound(VI) thus obtained is isolated by conventional methods.

The silyl compound can be employed in a molar ratio to compound offormula (VI), wherein R⁷ is lower alkyl of within the range from about1:3, preferably from about 1:1.5 to about 1:2. Similarly, the alkalimetal halide can be employed in a molar ratio to compound of formula(VI), wherein R⁷ is lower alkyl of within the range from about 1:3,preferably from about 1:1.5 to about 1:2.

The optical integrity of the proline fragment is maintained during theamide formation reaction i.e. both carbon atoms at position no. 2 and 4of the proline ring retain the (S)-configuration in compound of formula(VI), wherein R⁷ is lower alkyl or hydrogen.

(iii) Alkylation of compound of formula (VI) by reacting it with a haloester of structure (VII), wherein X is halogen selected from chlorine,bromine and iodine in presence of an organic solvent and a base for 2 to5 hrs at a temperature ranging from about 0 to 100° C. to give thephosphinylalkanoyl ester (II^(a)), wherein R⁸ has the same meaning asdefined earlier.

The phosphinic acid ester (VI), wherein R⁷ is hydrogen can be employedin a molar ratio to the halo ester (VII) of within the range of about1:4, preferably from about 1:1.5 to about 1:2. The solvents in which thereaction can be carried out include acetonitrile, dichloromethane,dichloroethane, ethylacetate, N,N-dimethylacetamide, N,N-dimethylformamide, tetrahydrofuran, toluene, xylene.

Dichloromethane, ethyl acetate, toluene are xylene preferred solvents.

The organic bases that can be employed include triethylamine,tripropylamine, pyridine, DBU and N-methyl morpholine, withtriethylamine preferred. The bases can be employed in a molar ratio tothe hydroxy compound (VI), wherein R⁷ is hydrogen of within the range ofabout 1:4, preferably from about 1:1.5 to about 1:2. The reaction ispreferably carried out a temperature ranging from 5 to 25° C.

The compound (II^(a)) can be isolated from the reaction mixture bystandard methods and subjected to deprotection of the group R⁸.Alternatively, a solution of compound of formula (II^(a)) in an organicsolvent obtained after work-up of the reaction can without isolation ofthe compound be used for the deprotection.

(iv) Compound of formula (II^(a)), obtained as an oil or a solution ofthe same without isolation from the previous step is subjected tohydrogenolysis for removal of the carboxylic acid protective group R⁸ bytreatment with hydrogen in the presence of a hydrogenation catalyst,such as palladium on charcoal, or other conventional palladium catalystsin presence of a solvent to give fosinopril of formula (II) obtained asan oil after isolation.

The reaction can be carried out in a solvent selected from acetonitrile,ethanol, ethyl acetate, methanol, N,N-dimethyl acetamide, N,N-dimethylformamide, tetrahydrofuran, toluene and xylene with, ethanol, ethylacetate toluene and xylene preferred.

Out of the sixteen possible isomers, compound (II) of the presentinvention is obtained as a mixture of four isomers only, since carbonatoms no. 2 and 4, carrying the carboxylic acid and cyclohexyl group,respectively have a definite configuration i.e. both have the(S)-configuation. There are two other chiral centres in the molecule andeach has its own configuration, classified as (R)- or (S)-. This inturn, gives rise to four isomers, since the first centre may be (R)- or(S)- and so may be the second.

Thus, the four isomers formed at the two chiral centres for compound(II) can be classified as,

a) one in which the Phosphorous-oxygen linkage has the (R)-configurationand the C(12)-C(13) linkage has the (S)-configuration i.e. compound offormula II A (SRSS-configuration),

b) one in which the Phosphorous-oxygen linkage has the (S)-configurationand the C(12)-C(13) linkage has the R)-configuration i.e. compound offormula II B (RSSS-configuration),

c) one in which the Phosphorous-oxygen linkage has the (R)-configurationand the C(12)-C(13) linkage has the (R)-configuration i.e. compound offormula II C(RRSS-configuration) and

d) one in which the Phosphorous-oxygen linkage has the (S)-configurationand the C(12)-C(13) linkage has the (S)-configuration i.e. compound offormula II D (SSSS-configuration).

The starting compounds utilised in the invention, viz. compounds offormula (IV) and (V) are obtained by methods known in the art.

These four isomers A, B, C and D are not mirror images of each otheri.e. they are diastereomers and not enantiomers. Diastereomers differ intheir physical and chemical properties, solubilities and reactivity.

This is specially so when stereoelectronic factors control the course ofreaction.

This aspect, specially the difference in solubility behaviour ofdiastereomers is used to advantage in the present invention to separatethe desired isomer of fosinopril (II A) from a mixture of fourdiastereomers (II A), (II B), (II C) and (II D). The solubility profileof the individual diastereomers in the mixture in various solvents isnot very different, but, however, becomes more pronounced when they areconverted to a salt, specially salts with alkali metals and amines.

In general, the formation of alkali metal salts can be achieved bymixing together the mixture of four diastereomers in a suitable solventwith an alkali metal carrier for one to four hours. Solvents in whichthe diastereomeric mixture of compounds is soluble can be used. Theseinclude, acetone, acetonitrile, dichloromethane, dichloroethane,dioxane, ethyl acetate, methyl ethyl ketone, methyl isobutyl ketone,N,N-dimethyl acetamide, N,N-dimethyl formamide, tetrahydrofuran, tolueneand xylene.

The alkali metals can be selected from sodium, potassium and cesium. Thealkali metal carriers that can be employed are those commonly used forthe alkali metal exchange and include carbonates, hydrogen carbonatesand ethyl hexanoates of the respective alkali metals.

The alkali metal exchange can be accomplished under anhydrous or nearanhydrous conditions in the absence of water when alkali metals salts ofethyl hexanoate is used. Water as present in the solvents employed isthe only source of water. When alkali metal carbonates and alkali metalhydrogen carbonates are used water as required to dissolve the salts isnecessary for the exchange.

The reaction can be carried from about −50 to 50° C., preferably fromabout −20 to 20° C.

The alkali metal carrier can be employed in a molar ratio to thediastereomeric mixture of compounds (II A), (II B), (II C) and (II D) ofwithin the range of from about 1 to 3, preferably in the range of about1 to 1.5

In a preferred aspect of the invention the separation of the desiredisomer (II A) from the mixture of four diastereomers (IIA), (II B), (IIC) and (II D) can be achieved in one step as summarised in Scheme-III byformation of the cesium salt, followed by crystallisation.

Accordingly, the mixture of diastereomers is mixed with a cesium salt ina suitable solvent mentioned earlier. Upon crystallisation from asuitable solvent or a mixture of solvents the cesium salt of thediastereomer (II A) separates out in a highly pure form.

Although, other alkali metal salts can be prepared, cesium alone is themost specific and the most preferred salt since it achieves clearseparation of the desired diastereomer in one single crystallisation.

The crystallisation of the cesium salt is preferably carried out insolvents selected from acetone, acetonitrile, dichloromethane,diisopropyl ether, ethyl acetate and tertiary butyl methyl ether ormixtures thereof having a water content in the range of about 1 to 10moles of the cesium salt of compound (II A)/(II B)/(II C)/(II D).Preferably, when water is in the range of about 2 to 5 moles the cesiumsalt of diastereomer (II A) crystallises out smoothly as the fosinoprilcesium salt dihydrate of formula (III A).

When amount of water is below the preferred molar range, the compound(II A) does not crystallise out properly and tends to stick. When amountof water is higher than the preferred range considerable amount ofcompound (III A) is lost to the mother liquor during filtration of theproduct.

The fosinopril cesium salt dihydrate (III A) is isolated by filtrationand is obtained in high purity, of ranging from about 99.2 to 99.5%. Theproduct has distinct IR spectrum, ¹H NMR spectrum and X-ray (powder)diffraction pattern, which are different from that reported forfosinopril sodium. The TG thermogram of the product confirms that itcontains two molecules of water i.e. it is a dihydrate.

The IR spectrum, X-ray (powder) diffraction pattern, DSC and TGthermograms of compound (III A) are reproduced in FIG. 1, FIG. 2, FIG. 3and FIG. 4 respectively.

Alternatively, the separation can be achieved in multiple steps. In thefirst step, alkali metal salts of the mixture of four diastereomers(HA), (II B), (II C) and (II D with sodium and potassium are preparedand allowed to crystallise from any of the solvent mentionedhereinearlier, preferably from acetone, acetonitrile, dichloromethaneand ethyl acetate or a mixture of these solvents with diethyl ether anddiisopropyl ether. A mixture predominantly containing two of thediastereomers (II A) and (II C) as their alkali metal salts, viz. (IIA-ALKALI METAL SALT) and (II C-ALKALI METAL SALT), wherein the alkalimetal salt is sodium or potassium separate out, which can be isolated byfiltration and dried. Among the alkali metals, sodium is the mostpreferred, which separates the mixture of diastereomers (II A) and (IIC) obtained in a ratio of 0.53:0.47. The chemistry employed issummarised in Scheme-VI.

The mixture of two diastereomeric alkali metal salts (II A-ALKALI METALSALT) and (II C-ALKALI METAL SALT) can be further converted to thecorresponding free acid mixture of diasteroemers (II A) and (II C) bytreatment with an acid. Both inorganic and organic acids can be used toeffect the hydrolysis.

Preferably, the alkali metal hydrolysis is effected by mixing a solutionof the mixture of two diastereomers (II A-ALKALI METAL SALT) and (IIC-ALKALI METAL SALT) in a solvent selected from dichloromethane,dichloroethane, diethyl ether, diisopropyl ether, ethyl acetate, methylethyl ketone, methyl isobutyl ketone, N,N-dimethyl acetamide,N,N-dimethyl formamide, tetrahydrofuran, toluene and xylene with asolution of potassium hydrogen sulfate in water at a temperature rangingfrom 5 to 35° C. at acidic pH in the range of about 1.0 to 4.0,preferably in the range of about 2.0 to 2.5. Evaporation of the solventgives the mixture of two diastereomers (II A) and (II C) as an oil.

Further separation of mixture of two diastereomers (II A) and (II C) canbe accomplished in two ways as summarised in Scheme-VII.

In one of the ways, the mixture of two diastereomeric free acids (II A)and (II C) can be mixed with an alkali metal salt in the presence of asolvent to form the corresponding alkali metal salt, from which the twodiastereomers can be separated by preferential crystallisation of onediastereomer. The alkali metal salts that can be used include sodium,potassium and cesium. Among these again cesium is the most specific andthe most preferred salt since it achieves clear separation of the twodiastereomers.

In the other method, the mixture of two diastereomers (II A) and (II C)can be reacted with an amino compound in an organic solvent to form thecorresponding amine salt. The amino compounds that can be used forforming the salt are selected from 2-amino-2-methyl-1-propanol,(+)-D-2-amino butanol, nicotinamide, dicyclohexyl amine and1-adamantanamine, with 2-amino-2-methyl-1-propanol preferred. The saltformation can be carried out in a solvent selected from acetonitrile,diisopropyl ether, ethyl acetate and isopropyl acetate, at a temperatureranging from about −30 to +30° C.

Crystallisation of the amine salt thus obtained, from the same solventused for salt formation or a mixture with a co-solvent affords a solidcompound predominantly containing the unwanted diastereomer (II C),which is isolated by filtration. The mother liquor contains the desireddiastereomer (II A) contaminated with about 10% of diastereomer (II C).Further upgradation of the product recovered from the mother liquor canbe accomplished by reacting the product mixture with a cesium salt asdescribed hereinearlier, followed by crystallisation to give compound(III A) in high purity.

All the methods summarised in Schemes-III, VI and VII can be employedfor achieving the separation. The single step separation summarised inis most preferred even though, more amounts of the expensive cesium saltneeds to be used rendering the process bit more costly than the othersgiven in Scheme-VI and VII, which, however, are more cumbersomerequiring multiple steps.

Compound of formula (III A), viz.[1[S*(R*),2α,4β]-4-cyclohexyl-1-[[[2-methyl-1-(1-oxopropoxy)propoxy)-4-phenylbutyl)phosphinyl]acetyl](trans)-4-cyclohexyl-L-proline,mono-cesium salt dihydrate is a novel crystalline compound havingdistinct X-ray (powder) diffraction pattern and is particularly a usefulintermediate for synthesis of fosinopril sodium of high purity as wouldbe evident from the method(s) described hereinbelow.

Preparation of Fosinopril Sodium (I) in Polymorphic Form-A fromFosinopril Cesium Salt Dihydrate (III A):

As summarised in Scheme-IV, the cesium salt (III A) is converted to thefree acid by treatment with a strong acid in a similar manner asdescribed earlier.

The free acid, i.e. fosinopril isomer (II A), is dissolved in an organicsolvent selected from acetone, acetonitrile, dichloromethane,dichloroethane, diethyl ether, diisopropyl ether, dioxane, ethylacetate, methyl ethyl ketone, methyl isobutyl ketone, N,N-dimethylacetamide, N,N-dimethyl formamide, tetrahydrofuran, toluene and xylene,with dichloromethane and ethyl acetate preferred and can be mixed with asodium metal carrier, selected from sodium ethyl hexanoate, sodiumcarbonate and sodium hydrogen carbonate for 1 to 4 hours, preferably 2hours at a temperature ranging from 5 to 35° C. to form the sodium salti.e. fosinopril sodium of formula (I).

When sodium ethyl hexanoate is employed as the sodium metal carrier, nowater need to be added to the reaction mixture. The reaction can becarried out under anhydrous or near anhydrous conditions. Water,however, may be present as normally associated with the solvent(s)employed. The water content present is normally below 0.2%.

Preferably, the water content is in the range of 0.03 to 0.05% of thetotal solvent(s).

When sodium hydrogen carbonate or sodium carbonate is employed as thesodium salt, then the reaction system is biphasic, one is a solventphase containing the dissolved fosinopril free acid isomer (II A) andthe other is the aqueous phase in which the alkali metal salt isdissolved. In 1 to 4 hours the exchange is completed, after which theorganic phase containing the sodium salt can be separated from theaqueous phase. The solution of fosinopril sodium in the organic solventafter separation usually has a water content in the range from about 1to 2%.

The fosinopril sodium thus formed can be isolated by standard methodsfrom the reaction mixture or preferably, without isolation can becrystallised from the same solvent or a mixture of solvents to give thepolymorphic Form-A of the sodium salt.

The crystallisation is accomplished by agitating a solution offosinopril sodium in any one of the solvents mentioned earlier or fromthe preferred solvents i.e. dichloromethane or ethyl acetate or amixture thereof over a long of period of time of about 10 to 24 hours,preferably 10 to 15 hours for polymorphic Form-A to crystallise out,which can be isolated by filtration.

When the sodium salt is not isolated and the solution containing thesame obtained by exchange with sodium ethyl hexanoate, either alone ormixed with another solvent is allowed to crystallise, the water contentin the solvent is normally below 0.2%, more precisely in the range ofabout 0.03 to 0.05%. When the solution containing fosinopril sodiumobtained by exchange with sodium carbonate or bicarbonate, either aloneor co-mixed with another solvent is allowed to crystallise, the watercontent in the solvent is normally in the range of 1-2%. Slowcrystallisation gives the polymorphic Form-A.

Alternatively, water can be azeotropically removed from the solution andbrought down to a level of 0.03 to 0.05% and then allowed to set forcrystallisation to give again the polymorphic Form-A.

The rate of crystallisation is the determining factor for formation ofthe polymorphic Form-A and not the solvent used or the water contentpresent in the solvent.

When insufficient time is given for crystallisation the crystalline formobtained is found to be contaminated with other polymorphic form i.e.Form-B.

The product obtained on slow crystallisation by employing the abovemethods i.e. from a solution containing water in the range of 0.03 to0.05% and from a solution containing water in the range from 1 to 2%have identical IR Spectrum, solid state ³¹P and ¹³C NMR specta and X-ray(powder) diffraction pattern, and conform to that reported forFosinopril Sodium polymorph-A in the literature.

The polymorphic Form-A can be isolated by filtration from the solvent orsolvent mixture from which it is crystallised and dried and has a purity>99%.

Conversion of Unwanted Isomers of Fosinopril Back to Fosinopril SodiumPolymorphic Form-A

A further object and aspect of the present invention is to provide amethod wherein the unwanted diasatereomers formed and separated in theprocesses mentioned herein earlier are converted back to fosinoprilsodium (I) as the polymorphic Form-A as summarised in Scheme-V.

The method comprises of first pooling together all the unwanteddiastereomers i.e. (II B), (II C) and (II D) contaminated with thediastereomer (II A) and their alkali metal salts thereof from the wastestream and subjecting the pooled mixture to hydrolysis to effectcleavage of the isobutyl propionate ester function attached to thephosphorous atom to give compound of formula (VIII)

The hydrolysis can be effected with a base or an acid. Moreover, thesame can be accomplished using a combination of trimethylchlorosilaneand an alkali metal halide like sodium iodide. Basic hydrolysis ispreferred since it is accompanied by minimum impurity formationfacilitating easy isolation of the product as a solid. The hydrolysiscan be effected at a temperature ranging from about −10 to 80° C.

The carboxylic acid function on the proline ring is then selectivelyesterified to give an ester of formula (VI), wherein R⁷ is hydrogen andR⁸ is a group easily removable by hydrogenolysis, and is preferablybenzyl or p-nitro benzyl group.

The esterification can be carried out by mixing together compound (VIII)in presence of a solvent and benzyl alcohol or p-nitro benzyl alcohol inpresence of an acid or a base.

The acidic esterification is accomplished by heating together compound(VIII) and benzyl alcohol or p-nitro benzyl alcohol and an acid selectedfrom p-toluene sulfonic acid and sulphuric acid in a hydrocarbon solventselected from cyclohexane, benzene and toluene at reflux temperature ofthe solvent for 10-15 hrs. The preferred solvent and acid arecyclohexane and p-toluenesulfonic acid respectively. The acid can beemployed in a ratio of 0.1 to 0.5 by weight of compound (VIII),preferable in the range of 0.1 to 0.25.

The basic esterification is accomplished by agitating together compound(VIII) and benzyl bromide or p-nitro benzyl bromide and a base selectedfrom triethylamine, potassium carbonate, sodium carbonate and N-methylmorpholine in presence of a solvent selected from acetone andacetonitrile at a temperature ranging from about 25-80° C. for 5-10hours.

The P—OH bond remains intact during the acidic and basic esterification.Compound (VI) can be isolated form the reaction mixture by conventionalmethods.

Compound (VI) is then alkylated with haloester of formula (VII) as perthe method described hereinearlier and after removal of the protectivegroup R⁸ by hydrogenolysis fosinopril (II) is obtained as a mixture offour diastereomers (II A), (II B), (II C) and (II D).

Fosinopril cesium dihydrate (III A) can then be prepared from themixture of diastereomers (II A), (II B), (II C) and (II D) by any of themethods summarised in Scheme-III, VI and VII, preferably Scheme-III. Thecompound (III A) is then converted to fosinopril sodium (I) inpolymorphic Form-A as per the methods summarised in Scheme-IV.

The following examples represent the preferred embodiments of theinvention, but however, should by no means be construed as limiting thescope of the invention.

EXAMPLE 11[{Methoxy(4-phenylbutyl)phosphinyl}acetyl]-(trans)-4-cyclohexyl-L-prolinebenzyl ester [Compound (VI), wherein R⁷ is methyl]

(trans)-4-cyclohexyl-L-proline benzyl ester hydrochloride [(V), 100 gm,0.309 moles) was taken in a mixture of dichloromethane (1050 ml) andwater (468 ml) and cooled to 5-10° C. Aqueous ammonia solution (25%) wasslowly added at the same temperature till the pH becomes 9.5-9.8. Theorganic phase was separated, washed with brine (200 ml) andconcentrated. The residue was dissolved in tetrahydrofuran (300 ml) andthe solution of (trans)-4-cyclohexyl-L-proline benzyl ester kept readyfor the addition in the next phase.

[Methoxy(4-phenylbutyl)phosphinyl]acetic acid [(IV, R⁷ is methyl), 98.2gm, 0.363 moles) was dissolved in tetrahydrofuran (1000 ml) undernitrogen atmosphere and cooled to −20° C. N-methyl morpholine (55 gm,0.544 moles) was added, followed by pivaloyl chloride (43.9 gm, 0.364moles) at the same temperature. The reaction mixture was stirred for 0.5hr and then cooled to −40° C. The solution of the(trans)-4-cyclohexyl-L-proline benzyl ester in tetrahydrofuran was addedat the same temperature and stirred for 1 hr. The reaction mixture wasconcentrated and diluted with ethyl acetate (700 ml). To this was added10% aqueous sodium bicarbonate solution (150 ml) and stirred for 10mins. The organic phase was separated, washed with 1N HCl (200 ml),water (200 ml×2) and the solvent evaporated off to give 166.5 gm(quantitative) of the title compound as an oil.

IR(Neat): 2927.7, 2852.5, 1743.5, 1651.0, 1433.0, 1172.6 cm⁻¹

¹H NMR (CDCl₃): δ 7.4-7.1 (m, 10H, aromatic protons); 5.2-5.05 (m, 2H,—O—CH2—Ph); 4.7-4.5 (d, 1H, J=9 Hz. —CH—COOCH₂Ph); 4.0-3.85 (m, 1H);3.8-3.65 (m, 3H, —OCH ³ ); 3.4-2.5 (m, 5H, —P—CH ² —CO—, Ph—CH ² — and—N—CH—); 2.25-1.5 (m, 14H); 1.3-0.8 (m, 6H)

EXAMPLE 21[{Hydroxy(4-phenylbutyl)phosphinyl}acetyl]-(trans)-4-cyclohexyl-L-prolinebenzyl, ester [Compound (VI), wherein R⁷ is hydrogen]

1[{Methoxy(4-phenylbutyl)phosphinyl}acetyl]-(trans)-4-cyclohexyl-L-prolinebenzyl ester (VI), obtained in Example 1 (166.5 gm, 0.309 moles) wasdissolved in acetonitrile (1750 ml) and cooled to 10-15° C. Sodiumiodide (78.7 gm, 0.525 moles) and trimethyl silyl chloride (57 gm, 0.525moles) were added to the solution and agitated at the same temperaturefor 1.5 hrs. A 33% aqueous sodium carbonate solution was added to thereaction mixture and the pH adjusted to about 4.5. The solids werefiltered and the filtrate was concentrated and the residue was dissolvedin ethyl acetate (1165 ml) and stirred to get a clear solution. Theethyl acetate solution was washed with water (166 ml) and 5% aqueoussodium thiosulphate solution (166 ml). Water (166 ml) was added to theethyl acetate portion and pH of the mixture was adjusted to 8.4-8.5 byadding 33% aqueous sodium carbonate solution. The organic portion wasseparated and mixed with water (166 ml). Conc. HCl was added to themixture and the pH adjusted to 2.2-2.5. The organic phase was furtherseparated and the solvent evaporated off to give 138 gm (85%) of thetitle product as an oil.

IR (Neat): 2925.8, 2852.5, 1743.5, 1645.2, 1604.7, 1434.9, 1172.6, 960.5cm⁻¹

¹H NMR (CDCl₃): δ 7.4-7.1 (m, 10H, aromatic protons); 5.25-5.05 (m, 2H,—O—CH2—Ph); 4.7-4.55 (d, 1H, J=9 Hz, —CH—COOCH₂Ph); 4.0-3.8 (m, 1H,—N—CH—); 3.3-3.15 (m, 1H, —N—CH—); 3.0-2.5(m, 4H, —P—CH ² —CO— and Ph—CH² —); 2.2-1.5 (m, 14H); 1.3-0.7 (m, 6H)

EXAMPLE 31[{2-Methyl-1-(1-oxopropoxy)propoxy)-4-phenylbutyl}acetyl]-(trans)-4-cyclohexyl-L-prolinebenzyl ester [Compound (II^(a))]

1[{Hydroxy(4-phenylbutyl)phosphinyl}acetyl]-(trans)-4-cyclohexyl-L-prolinebenzyl ester (VI), obtained in Example 2 (64 gm, 0.122 moles) was takenin toluene (400 ml) and triethylamine (21.5 gm, 0.213 moles) was addedat 25° C. 1-Bromo isobutyl propionate [37 gm, 0.177 moles, Compound(VII)] was added and the reaction mixture was heated at 90-95° C. for 3hrs and cooled to room temperature. Water (150 ml) was added and stirredfor 20 mins. The organic phase was separated, washed with 0.1N HCl (100ml), dried over anhydrous magnesium sulfate and the solvent evaporatedoff to give 71.6 gm (90%) of the title product as an oil.

IR (Neat): 2925.8, 2852.5, 1747.4, 1651.0, 1434.9, 1174.6 cm⁻¹

¹H NMR (CDCl₃): δ 7.3-7.0 (m, 10H, aromatic protons); 6.3-6.1(m, 1H,O—CH—O); 5.25-5.0 (m, 2H, —O—CH2-Ph); 4.6-4.45 (m, 1H, —CH—COOCH₂Ph);4.1-3.6 (m, 1H); 3.45-2.65 (m, 3H, —P—CH ² —CO—, —N—CH—); 2.6-2.5 (m,2H, Ph—CH ² ); 2.4-2.15(m, 3H); 2.15-1.75(m,5H); 1.75-1.45 (m, 9H);1.3-0.7 (m, 15H)

EXAMPLE 41[{2-Methyl-1-(1-oxopropoxy)propoxy)-4-phenylbutyl}acetyl]-(trans)-4-cylohexyl-L-proline[Compound (II) as a mixture of four diastereomers (II A), (II B), (II C)and (II D)]

1[{2-Methyl-1-(1-oxopropoxy)propoxy)-4-phenylbutyl}acetyl]-(trans)-4-cyclohexyl-L-prolinebenzyl ester [(II^(a), obtained in Example 3) 79.6 gm, 0.122 moles) wastaken in toluene (240 ml) and transferred to a parr bottle and mixedwith 10% Pd/C (8 gm) added and the reaction mixture stirred under 65-70psi of Hydrogen gas pressure for 1.5 hrs. The palladium catalyst wasfiltered and the filtrate concentrated to give 68.6 gm (quantitative) ofthe title compound mixture of four diastereomers as an oil.

IR (Neat): 2925.8, 1755.1, 1651.0, 1604.7, 1450.4, 1174.6 cm⁻

¹H NMR (CDCl₃): δ 7.25-7.0 (m, 5H, aromatic protons); 6.3-6.1(m, 1H,O—CH—O); 4.6-4.5 (m, 1H, —CH—COOH); 4.05-3.7 (m, 2H); 3.5-2.7 (m, 3H);2.6-2.5 (m, 2H, PhCH ² ); 2.5-2.25(m, 3H); 2.2-1.8(m,5H); 1.8-1.4 (m,9H); 1.3-0.7 (m, 15H)

EXAMPLE 51[{2-Methyl-1-(1-oxopropoxy)propoxy)-4-phenylbutyl}acetyl]-(trans)-4-cyclohexylL-proline sodium salt [Mixture of Sodium salt of diastereomers (II A)and (II C)]

1[{2-Methyl-1-(1-oxopropoxy)propoxy)-4-phenylbutyl}acetyl]-(trans)-4-cyclohexyl-L-proline[mixture of four diastereomers (II A), (II B), (II C) and (II D),obtained in Example 4, 68.7 gm, 0.122 moles] was dissolved in ethylacetate (276 ml) and cooled to 10° C. 10% aqueous solution of sodiumbicarbonate (123 ml, 0.1464 moles) was added and stirred for 2 hrs. Theorganic portion was separated and concentrated under reduced pressure.Diisopropyl ether (310 ml) was added to the residue and stirred for 6hrs at 20° C. The solid which crystallises out was filtered and driedunder vacuum to give 22 gm of a compound mixture of sodium salt ofdiastereomers (II A) and (II C) in a ratio of 0.53:0.47 as a whitesolid.

IR (KBr): 2925.8, 2856.4, 1757.0, 1624.0, 1600.8, 1452.3, 1409.9, 950.8cm⁻¹

¹H NMR (CDCl₃): δ 7.3-7.05 (m, SF, aromatic protons); 6.35-6.2(m, 1H,O—CH—O); 4.5-4.35 (m, 1H, —CH—COONa); 3.95-3.72 (m, 1H); 3.4-2.85 (m,3H, —P—CH ² —CO—, —N—CH—); 2.7-2.55 (t, 2, PhCH ² ); 2.5-2.25(m, 3H);2.2-1.85(m,5H); 1.8-1.5 (m, 9H); 1.4-0.8 (m, 15H)

EXAMPLE 6[1[S*(R*)],2α,4β]-4-cyclohexyl-1-[[[2-methyl-1-(1-oxopropoxy)propoxy)-4-phenylbutyl}acetyl]-(trans)-4-cyclohexyl-L-prolinemono cesium salt dihydrate [Compound (III A)]: Via the sodium saltmixture

To a mixture of ethyl acetate (50 ml) and water (25 ml), the mixture ofsodium salt of diastereomers (II A) and (II C), obtained in Example 5 (5gm, 0.00854 moles) was added and cooled to 0-5° C. To this was added anaqueous solution of potassium hydrogen sulfate slowly till the pH isadjusted to 2.5. The organic phase was separated and the solventevaporated off. Diisopropyl ether (35 ml) was added to the residue andstirred to get a clear solution. To this was added an aqueous solutionof cesium carbonate (1.33 gm, 0.0041 moles in 0.6 ml water) at −10° C.and stirred for 2 hrs. The reaction mass was concentrated and theresidue mixed with diisopropyl ether (75 ml) and stirred at −10° C. foranother 2 hrs. The precipitated solids were filtered and the solidwashed with diisopropyl ether (25 ml). After drying the solid wasredissolved in dichloromethane (30 ml), mixed with diisopropyl ether (90ml) and stirred for 1 hr. The solid product was filtered and washed withdiisopropyl ether (30 ml) and dried to give 1.3 gm of the title compoundas a white solid, having purity of 99.5%.

IR (KBr): 3278.8, 2922.0, 2850.6, 1739.7, 1633.6, 1589.2, 1461.9,1396.4, 1215.1, 1186.1 cm⁻¹

¹H NMR (CD₃OD): δ 7.15-6.95 (m, 5H, aromatic protons); 6.15-6.05(m, 1H,O—CH—O); 4.28-4.2 (d, 1H, J=9 Hz, —CH—COOCs); 3.75-3.6(m, 1H, —NCH—);3.28-3.1 (m, 1H, —N—CH—); 3.08-2.68(m, 2H, P—CH ² —CO—); 2.58-2.4 (t,2H, Ph—CH ² ); 2.35-2.15(m, 3H); 2.1-1.7(m,5H); 1.7-1.35 (m, 9H);1.25-0.65 (m, 15H)

EXAMPLE 7[1[S*(R*)],2α,4β]-4-cyclohexyl-1-[[[2-methyl-1-(1-oxopropoxy)propoxy)-4-phenylbutyl}acetyl]-(trans)-4-cyclohexyl-L-prolinemono cesium salt dihydrate [Compound (III A)]

Corresponding acid of the mixture of sodium salt of two diastereomers(II A) and (II C) [5 gm, 0.00854 moles] was prepared exactly asdescribed in Example 6. Dichloromethane (25 ml) was added to the residueand stirred to get a clear solution. Cesium Carbonate (1.33 gm, 0.0041moles) was dissolved in water (0.6 ml) and added to the solution at −10°C. and the mixture stirred for 2 hrs. The reaction mass was concentratedand the residue mixed with diisopropyl ether (75 ml) and stirred foranother 2 hrs at −10° C. The precipitated solid was filtered and thesolid washed with diisopropyl ether (25 ml). After drying the solid wasredissolved in dichloromethane (30 ml), mixed with diisopropyl ether (90ml) and stirred for 1 hr. The solid product was filtered and washed withdiisopropyl ether (30 ml). It was dried to give 1.3 gm of the titlecompound as a white solid, having purity of 99.5%.

EXAMPLE 8[1[S*(R*)],2α,4β]-4-cyclohexyl-1-[[[2-methyl-1-(1-oxopropoxy)propoxy)-4-phenylbutyl}acetyl]-(trans)-4-cyclohexyl-L-prolinemono cesium salt dihydrate [Compound (III A)]

Corresponding acid of the mixture of sodium salt of two diastereomers(II A) and (II C) [5 gm, 0.00854 moles] was prepared exactly asdescribed in Example 6 Ethyl acetate (25 ml) was added to the residueand stirred to get a clear solution. Cesium Carbonate (1.33 gm, 0.0041moles) was dissolved in water (0.6 ml) and added to the solution of thecompound at −10° C. and the mixture stirred for 2 hrs. The reaction masswas concentrated and the residue was mixed with ethyl acetate (35 ml)and stirred at −10° C. for another 2 hrs. The crystallised solid wasfiltered, dried and redissolved in dichloromethane (30 ml), mixed withdiisopropyl ether (90 ml) and stirred for 1 hr. The solid product wasfiltered and washed with diisopropyl ether (30 ml) and dried to give 1gm of the title compound as white solid, having purity of 99.5%.

EXAMPLE 9[1[S*(R*)],2α,4β]-4-cyclohexyl-1-[[[2-methyl-1-(1-oxopropoxy)propoxy)-4-phenylbutyl}acetyl]-(trans)-4-cyclohexyl-L-prolinemono cesium salt dihydrate [Compound (III A)]

Cesium salt of the diastereomers (II A) and (II C) was prepared fromtheir sodium salt (5 gm, 0.00854 moles) exactly as in Example 6. Thedried solid was dissolved in dichloromethane (30 ml) to which ethylacetate (90 ml) was added and the mixture stirred for 1 hr. The solidwhich crystallises out was filtered and dried to yield 1 gm of the titlecompound as a white solid, having purity of 99.5%.

EXAMPLE 10[1[S*(R*)],2α,4β]-4-cyclohexyl-1-[[[2-methyl-1-(1-oxopropoxy)propoxy)-4-phenylbutyl}acetyl]-(trans)-4-cyclohexyl-L-prolinemono cesium salt dihydrate [Compound (III A)]

Cesium salt of the diastereomers (II A) and (II C) was prepared fromtheir sodium salt (5 gm, 0.00854 moles) exactly as in Example 6. Thedried solid was dissolved in acetone (40 ml) at 40-45° C. and thesolution cooled 20-25° C. and stirred for 1 hr. The solid whichcrystalises out product was filtered and dried to give 1.1 gm of thetitle compound as a white solid, having purity of 99.5%.

EXAMPLE 11[1[S*(R*)],2α,4β]-4-cyclohexyl-1-[[[2-methyl-1-(1-oxopropoxy)propoxy)-4-phenylbutyl}acetyl]-(trans)-4-cyclohexyl-L-prolinemono cesium salt dihydrate [Compound (III A)]

Cesium salt of the diastereomers (II A) and (II C) was prepared fromtheir sodium salt (5 gm, 0.00854 moles) exactly as in Example 6. Thedried solid dissolved in acetonitrile (30 ml, water content 2%) at40-45° C. and then further cooled 20-25° C. and stirred for 1 hr. Thesolid which crystallises out was filtered and dried to give 1.1 gm ofthe title compound as a white solid, having purity of 99.5%.

EXAMPLE 12[1[S*(R*)],2α,4β]-4-cyclohexyl-1-[[[2-methyl-1-(1-oxopropoxy)propoxy)-4-phenylbutyl}acetyl]-(trans)-4-cyclohexyl-L-prolinemono cesium salt dihydrate [Compound (III A)]: Via the amine saltmixture PART A:1[{2-Methyl-1-(1-oxopropoxy)propoxy)-4-phenylbutyl}acetyl]-(trans)-4-cyclohexyl-L-proline,2-amino-2-methyl-1-propanol salt [Mixture of 2-amino-2-methyl-1-propanolsalt of diastereomers (II A) and (II C)]

To a mixture of ethyl acetate (50 ml) and water (25 ml), the mixture ofsodium salt of diastereomers (II A) and (II C), obtained in Example 5 (5gm, 0.00854 moles) was added and cooled to 0-5° C. To this was added anaqueous solution of potassium hydrogen sulfate slowly till the pH isadjusted to 2.5. The organic layer was separated, washed with water andbrine and was cooled to 5° C. To the cooled solution was added2-Amino-2-methyl-1-propanol (0.769 gm, 0.00863 moles) and stirred for 45mins. The reaction mass was concentrated and diisopropyl ether (50 ml)was added to the residue and stirred for 1 hr at 0-5° C. Theprecipitated solid was filtered and washed with diisopropyl ether (20ml) and dried. The dried solid was stirred with acetonitrile (40 ml) at0-5° C. for 1 hr and filtered. The solid was washed with acetonitrile(20 ml). The solid amine salt was again stirred with ethyl acetate (20ml, water content 1.5%) for 30 mins. Filtration gave 1 gm of solid,predominantly containing the 2-amino-2-methyl-1-propanol salt ofdiastereomer (II C).

The diisopropyl ether and acetonitrile mother liquors were combined andconcentrated to give 2.5 gm of a residue consisting of a mixture ofabout 90% of the 2-amino-2-methyl-1-propanol salt of diastereomer (II A)and about 10% of the 2-amino-2-methyl-1-propanol salt of diastereomer(II C).

PART B: Preparation of Cesium Salt from the Amine Salt

The solid amine salt obtained from the combined mother portion in Part Aconsisting of a mixture of about 90′/o of the2-amino-2-methyl-1-propanol salt of diastereomer (II A) and about 10% ofthe 2-amino-2-methyl-1-propanol salt of diastereomer (II C) was mixedwith ethyl acetate (20 ml) and water (10 ml) and cooled to 0-5° C. Tothis was slowly added an aqueous solution of sodium hydrogen sulfatetill pH of the reaction mixture is adjusted to 2.5. The organic phasewas separated, washed with water, brine and the solvent evaporated off.

The residue is converted to the cesium salt as per any of the methoddescribed in Examples 6 to 11 to give the title compound (III A).

EXAMPLE 13[1[S*(R*)],2α,4β]-4-cyclohexyl-1-[[[2-methyl-1-(1-oxopropoxy)propoxy)-4-phenylbutyl}acetyl]-(trans)-4-cyclohexyl-L-prolinemono cesium salt dihydrate [Compound (III A)]: directly from the mixtureof four diastereomers

To a solution of 2.4 gm (0.00426 moles) of the mixture of fourdiastereomers (II A), (II B), (II C) and (II D) in dichloromethane (24ml) cooled to −20±2° C. was added a solution of 0.66 gm (0.0041 moles)of cesium carbonate in 0.26 ml of water and the mixture stirred at−20±2° C. for 4 hrs. The reaction mixture was concentrated and theresidue was dissolved in diisopropyl ether (108 ml) and stirred at −10°C. for 2 hrs. The solid which crystallises out was filtered and washedwith diisopropyl ether (15 ml) and dried. The dried solid (0.5 gm) isredissolved in dichloromethane (5 ml) and mixed with diisopropyl ether(15 ml) and stirred for 3 hrs. The solid which crystallises out wasfiltered, washed with diisopropyl ether and dried to give 0.4 gm of thetitle compound as a white solid, having purity of 99.5%.

EXAMPLE 14[1[S*(R*)],2α,4β]-4-cycohexyl-1-[[[2-methyl-1-(1-oxopropoxy)propoxy)-4-phenylbutyl}acetyl]-(trans)-4-cyclohexyl-L-prolinesodium salt Polymorph A [Compound (I)]

Fosinopril cesium, viz.[1[S*(R*)],2α,4β]-4-cyclohexyl-1-[[[2-methyl-1-(1-oxopropoxy)propoxy)-4-phenylbutyl}acetyl]-(trans)-4-cyclohexyl-L-prolinecesium salt dihydrate (III A) [20 gm, 0.0288 moles, obtained from any ofthe Examples 6-13] was taken in a mixture of dichloromethane (270 ml)and water (130 ml) and cooled to 0-5° C. To this was added an aqueoussolution of potassium hydrogen sulfate slowly till the pH is adjusted to2.5. The organic phase was separated and the solvent evaporated off, Theresidue was redissolved in dichloromethane (170 ml) and the solution wascooled to 10° C. and mixed with 10% aqueous solution of sodiumbicarbonate (23 ml, 0.02735 moles) and stirred for 2 hrs. The organicphase was separated and water was azeotropically removed from thesolvent till the water content becomes about 0.03%. To the solution wasadded ethyl acetate (250 ml) and the solution stirred for 15 hrs. Thesolid which crystallises out was filtered and washed with ethyl acetate(40 ml) and dried under vacuum at 40° C. for 6 hrs to give 14.5 gm (86%)of fosinopril sodium (I) as polymorphic Form-A as a white solid, havingpurity of 99.5%.

IR (KBr): 2924.9, 2856.2, 1759.3, 1622.6, 1600.2, 1452.1, 1409.1, 1384.6cm⁻¹

¹H NMR (CD₃OD): δ 7.15-6.95 (m, 5H, aromatic protons); 6.15-6.05(m, 1H,O—CH—O); 4.28-4.2 (d, 1H, J=9 Hz, —CH—COONa); 3.75-3.6 (m, 1H, —NCH—);3.28-3.1 (m, 1H, —N—CH—); 3.08-2.68(m, 2H, P—CH ² —CO—); 2.58-2.4 (t,2H, Ph—CH ² ); 2.35-2.15(m, 3H); 2.1-1.7(m,5H); 1.7-1.35 (m, 9H);1.25-0.65 (m, 15H)

13C CP-MAS at 8 KHz: 173.3, 167.5, 160.1, 137.95, 120.6, 109.74, 103.98,95.98, 74.32, 60.87, 60.46, 59.32, 56.78, 49.45, 47.8, 45.4, 38.8; 35.9,32.5, 28.7, 23.5, 20.9, 20.1, 16.2, 15.08, 3.42

31 P HPDEC at 8 KMz: 53.355

[α]_(D) at 23° C.-5.1 (c=2,MeOH)

EXAMPLE 15[1[S*(R*)],2α,4β]-4-cyclohexyl-1-[[[2-methyl-1-(1-oxopropoxy)propoxy)-4-phenylbutyl}acetyl]-(trans)-4-cyclohexyl-L-prolinesodium salt Polymorph A [Compound (I)]

Fosinopril acid was prepared from the cesium salt dihydrate [(III A), 1gm, 0.00144 moles] exactly as described in Example 14. The residue wasdissolved in dichloromethane (10 ml) and mixed with 10% aqueous solutionof sodium bicarbonate (1.15 ml, 0.00136 moles) and stirred for 2 hrs.The organic phase was separated and water was azeotropically removedfrom the solvent till the water content becomes about 0.03%. The volumeof the reaction mixture was brought down to ca. 5 ml and the solutionwas stirred for 15 hrs. The solid which crystallises out was filteredand dried under vacuum at 40° C. for 6 hrs to give 0.5 gm of the titlecompound as a white solid, having purity of 99.5%.

EXAMPLE 16[1[S*(R*)],2α,4β]-4-cyclohexyl-1-[[[2-methyl-1-(1-oxopropoxy)propoxy)-4-phenylbutyl}acetyl]-(trans)-4-cyclohexyl-L-prolinesodium salt Polymorph A [Compound (I)]

Fosinopril cesium, viz.[1[S*(R*)],2α,4β]-4-cyclohexyl-1-[[[2-methyl-1-(1-oxopropoxy)propoxy)-4-phenylbutyl}acetyl]-(trans)-4-cyclohexyl-L-prolinecesium salt dihydrate (III A) [6 gm, 0.008638 moles, obtained from anyof the Examples 6-13] was taken in a mixture of dichloromethane (80 ml)and water (40 ml) and cooled to 0-5° C. To this was added an aqueoussolution of potassium hydrogen sulfate slowly till the pH is adjusted to2.5. The organic phase was separated, washed with water (25 ml×2) andthe solvent evaporated off. The residue was dissolved in dichloromethane(50 ml) and water was azeotropically removed till the water content inthe solvent comes to ca. 0.03%. To this was added a solution of sodiumethyl hexanoate (1.36 gm, 0.008206 moles) in ethyl acetate (65 ml, watercontent ca.0.03%) and the mixture stirred for 15 hrs. The solid whichcrystallises out was filtered, washed with ethyl acetate (40 ml) anddried under vacuum at 40° C. for 6 hrs to give 4.3 gm (86%) of the titlecompound as a white solid, having purity of 99.5%.

EXAMPLE 17[1[S*(R*)],2α,4β]-4-cyclohexyl-1-[[[2-methyl-1-(1-oxopropoxy)propoxy)-4-phenylbutyl}acetyl]-(trans)-4-cyclohexyl-L-prolinesodium salt Polymorph [Compound (I)]

Fosinopril cesium, viz.[1[S*(R*)],2α,4β]-4-cyclohexyl-1-[[[2-methyl-1-(1-oxopropoxy)propoxy)-4-phenylbutyl}acetyl]-(trans)-4-cyclohexyl-L-prolinecesium salt dihydrate (III A) [1 gm, 0.00144 moles, obtained from any ofthe Examples 6-13] was taken in a mixture of dichloromethane (80 ml) andwater (40 ml) and cooled to 5° C. To this was added an aqueous solutionof potassium hydrogen sulfate slowly till the pH is adjusted to 2.5. Theorganic phase was separated, washed with water (25 ml×2) and the solventevaporated off. The residue was dissolved in tetrahydrofuran (10 ml) andmixed with a solution of sodium ethyl hexanoate (0.227 gm, 0.00137moles) in tetrahydrofuran (5 ml) and the mixture stirred for 15 hrs. Thesolid which crystallises out was filtered and washed withtetrahydrofuran (5 ml) and dried under vacuum at 40° C. for 6 hrs togive 0.7 gm (85%) of the title compound as a white solid, having-purityof 99.5%.

EXAMPLE 18[1[S*(R*)],2α,4β]-4-cyclohexyl-1-[[[2-methyl-1-(1-oxopropoxy)propoxy)-4-phenylbutyl}acetyl]-(trans)-4-cyclohexyl-L-prolinesodium salt Polymorph A [Compound (I)]

Fosinopril cesium, viz.[1[S*(R*)],2α,4β]-4-cyclohexyl-1-[[[2-methyl-1-(1-oxopropoxy)propoxy)-4-phenylbutyl}acetyl]-(trans)-4-cyclohexyl-L-prolinecesium salt dihydrate (III A) [1 gm, 0.00144 moles, obtained from any ofthe Examples 6-13] was taken in a mixture of dichloromethane (80 ml) andwater (40 ml) and cooled to 0-5° C. To this was added an aqueoussolution of potassium hydrogen sulfate slowly till the pH is adjusted to2.5. The organic phase was separated, washed with water (25 ml×2) andthe solvent evaporated off. The residue was dissolved in toluene (10 ml)and mixed with a solution of sodium ethyl hexanoate (0.227 gm, 0.00137moles) in ethyl acetate (16 ml) and the mixture stirred for 15 hrs. Thesolid which crystallises out was filtered and washed with ethyl acetate(5 ml) and dried under vacuum at 40° C. for 6 hrs to give 0.7 gm (85%)of the title compound as a white solid, having purity of 99.5%.

EXAMPLE 191[{Hydroxy(4-phenylbutyl)phosphinyl}acetyl]-(trans)-4-cyclohexyl-L-proline[compound (VIII)]

38 gm (0.0547 moles) of1[{2-Methyl-1-(1-oxopropoxy)propoxy)-4-phenylbutyl}acetyl]-(trans)-4-cyclohexyl-L-prolinecesium salt as contained in the mother liquor from Example 6 was mixedwith water (114 ml) and the mixture cooled to 0-5° C. To this was addedan aqueous solution of sodium hydroxide (4.5 gm, 0.112 moles) in 36 mlof water and the mixture stirred for 3 hrs. Ethyl acetate (76 ml) wasadded to the reaction and the pH adjusted to 2.0-2.1 by addition ofConc. HCl. The organic phase was separated and the solvent evaporatedunder reduced pressure. The residue was mixed with diisopropyl ether(190 ml) and stirred for 3 hrs. The precipitated solid was filtered,washed with diisopropyl ether and dried at 40° C. to give 20 gm (84%) ofthe title compound as a white solid.

IR (KBr): 2925.8, 2852.5, 1716.5, 1625.9, 1604.7, 1450.4, 1136.0 cm⁻¹

¹H NMR (CDCl₃): δ 7.2-6.95 (m, 51 aromatic protons); 4.5-4.4 (m, 1H,—CH—COOH); 3.85-3.55 (m+bs, 1H, P—OH and —COOH); 3.05-2.85 (m, 3H, —P—CH² —CO— and —N—CH—); 2.52-2.42 (t, 2H, Ph—CH ² ); 2.28-1.4 (m, 14H);1.3-0.7 (m, 6H)

EXAMPLE 201[{Hydroxy(4-phenylbutyl)phosphinyl}acetyl]-(trans)-4-cyclohexyl-L-proline[compound (VIII)]

3.9 gm (0.0066 moles) of1[{2-Methyl-1-(1-oxopropoxy)propoxy)-4-phenylbutyl}acetyl]-(trans)-4-cyclohexyl-L-prolinesodium salt as contained in the mother liquor from Example 5 was mixedwith water (16 ml) and cooled to 0-5° C. To this was added an aqueoussolution of sodium hydroxide (0.546 gm, 0.0136 moles) in 8 ml of waterand the mixture stirred for 3 hrs. Ethyl acetate (76 ml) was added tothe reaction and the pH adjusted to 2.0-2.1 by addition of Conc. HCl.The organic phase was separated and the solvent evaporated under reducedpressure and the residue was mixed with diisopropyl ether (3.0 ml) andstirred for 3 hrs. The precipitated solid was filtered, washed withdiisopropyl ether and dried at 40° C. to give 1.9 gm of the titlecompound as a white solid.

EXAMPLE 211[{Hydroxy(4-phenylbutyl)phosphinyl}acetyl]-(trans)-4-cyclohexyl-L-prolinebenzyl ester [Compound (VI), wherein R⁷ is hydrogen and R⁸ is benzylgroup]

To a solution of1[{Hydroxy(4-phenylbutyl)phosphinyl}acetyl]-(trans)-4-cyclohexyl-L-proline[(VIII), 50 gm, 0.1149 moles) in cyclohexane (500 ml) was addedp-toluene sulfonic acid monohydrate (10 gm) and benzyl alcohol (14.9 gm,0.1379 moles) and refluxed with simultaneous azeotropic removal of waterfor 14 hrs. Cyclohexane was distilled out and to the residue ethylacetate (250 ml) was added and stirred to get a clear solution. Theethyl acetate solution was washed with water (50 ml×2), dried overanhydrous magnesium sulfate and the solvent evaporated to give 59 gm(98%) of the title compound as an oil.

IR (Neat): 2925.8, 2852.5, 1743.5, 1645.2, 1604.7, 1434.9, 1172.6, 960.5cm⁻¹

¹H NMR (CDCl₃): δ 7.4-7.1 (m, 10H, aromatic protons); 5.25-5.05 (m, 2H,—O—CH2—Ph); 4.7-4.55 (d, 1H, J=9 Hz, —CH—COOCH₂Ph); 4.0-3.8 (m, 1H,—N—CH—); 3.3-3.15 (m, 1H, —N—CH—); 3.0-2.5(m, 4H, —P—CH ² —CO— and Ph—CH² —); 2.2-1.5 (m, 14H); 1.3-0.7 (m, 6H)

EXAMPLE 221[{Hydroxy(4-phenylbutyl)phosphinyl}acetyl]-(trans)-4-cyclohexyl-L-prolinebenzyl ester [Compound (VI), wherein R⁷ is hydrogen and R⁵ is p-nitrobenzyl group]

To a solution of1[{Hydroxy(4-phenylbutyl)phosphinyl}acetyl]-(trans)-4-cyclohexyl-L-proline[(VIII), 0.5 gm, 0.001149 moles) in acetonitrile (5 ml) was addedtriethylamine (0 25 gm, 002528 moles) and p-nitro benzyl bromide (0.3gm, 0.001378 moles) added and stirred for 6 hrs. Acetonitrile wasevaporated and the residue was dissolved in dichloromethane (10 ml),washed with water and dried over anhydrous magnesium sulfate. Thesolvent was evaporated and crystallisation of the residue from a mixtureof ethylacetate and hexane gave 0.35 gm of the title compound as whitesolid.

IR (Neat): 2929.7, 2852.5, 1747.4, 1651.0, 1608.5, 1525.6, 1440.7,1137.9 cm⁻¹

¹H NMR (CDCl₃): δ 8.1-8.0 (d, 2H, J=7.5 Hz, aromatic protons); 7.4-7.3(d, 2H, J=7.5 Hz, aromatic protons); 7.15-6.95 (m, 5H, aromaticprotons); 5.2-5.0 (m, 2H, —O—CH2—PNB); 4.4-4.3 (d, 1H, —CH—COO—);3.85-3.7 (t, 1H); 3.15-3.05 (t, 1H); 2.95-2.75 (m, 2H); 2.55-2.4(t, 2H,Ph-CH ² —); 2.1-1.4 (m, 14H); 1.15-0.7 (m, 6H) TABLE 1 X-ray (powder)diffraction pattern of the compound of formula (IIIA) □ d I/I₁ 4.300020.53270 14 4.6761 18.88206 65 4.9800 17.73046 16 6.9383 12.72990 49.0000 9.81785 18 9.3400 9.46121 19 10.2591 8.61556 8 11.1843 7.90485 1713.5200 6.54401 14 13.8600 6.38423 19 14.3200 6.18017 9 14.9000 5.940883 15.3246 5.77722 99 15.9203 5.56236 39 16.6550 5.31861 8 17.36005.10417 6 17.8400 4.96791 23 18.3005 4.84392 32 19.2117 4.61618 3319.8200 4.47586 7 20.1837 4.39602 45 20.6800 4.29163 26 21.0400 4.2190017 21.6800 4.09588 6 21.9943 4.03805 26 22.5400 3.94151 26 22.86243.88665 100 23.2802 3.81784 82 23.8800 3.72328 4 24.2400 3.66880 2124.5200 3.62753 13 25.0400 3.55337 27 25.4000 3.50381 18 25.7800 3.4530231 26.3983 3.37353 13 26.7986 3.32404 11 27.5286 3.23753 6 27.90553.19465 14 28.2600 3.15538 9 28.8506 3.09211 20 29.3015 3.04555 530.0261 2.97368 7 30.8493 2.89618 49 31.1800 2.86621 5 31.5400 2.83432 431.7930 2.81234 19 33.2926 2.68901 44 34.0710 2.62933 4 34.4622 2.6003711 35.3308 2.53841 17 36.1300 2.48407 10 37.7758 2.37954 27 38.31962.34702 5 38.5848 2.33149 4 39.3575 2.28748 9 39.8263 2.26163 10 40.59672.22047 13 41.1000 2.19443 3 42.3183 2.13403 8 43.7725 2.06645 8 43.98002.05718 4 45.1650 2.00592 3 45.5060 1.99168 4 46.3200 1.95856 4 46.52001.95060 4 47.4679 1.91384 3

1-22. (canceled)
 23. The process of claim 1 wherein any cesium salts ofdiastereomers: (II B), (II C) and (II D) contained in the waste streamobtained obtained in Step (b), (v) are converted into said compound offormula (II A) by d) ix) hydrolysing the mixture of diastereomers (IIB),(II C) and (II D) contained in the waste stream of Step (b), (v) to givecompound of formula (VIII)

X) selective esterifying the carboxylic acid group in compound (VIII) inpresence of a base or an acid and in presence of a solvent to givecompound of formula (VI)

wherein R⁷ is hydrogen and R⁸ is a group removable easily byhydrogenolysis as defined above. xi) reacting compound (VI) with acompound of formula (VII)

in the presence of a base and a solvent to give compound of formula(II^(a))

xii) deprotecting the group R⁸ in compound of formula (II^(a)) byreacting it with hydrogen in presence of palladium on carbon as catalystin presence of a solvent to give fosinopril as a mixture of fourdiastereomers (II A), (II B), (II C) and (II D) xiii) mixing togetherfosinopril mixture of four diastereomers (II A), (II B), (II C) and (IID) with a cesium metal carrier in the presence of a solvent andcrystallisation of the mixture of cesium salts thus formed from the samesolvent or a mixture of solvents containing 1-10 moles of water withrespect to compound (II A)/(II B)/(II C)/(II D) to give compound offormula (III A)

xiv) reacting compound of formula (III A) with an acid in the presenceof a solvent and water to give the fosinopril diastereomer (II A)

and e) converting said compound (II A) to fosinopril sodium polymorphicForm-A comprising xv) mixing together compound (II A) with a sodiummetal carrier in presence of a solvent or a mixture of solvents tofosinopril sodium of formula (I) and xvi) crystallisation of thefosinopril sodium of formula (I) thus formed in the same solvent ormixture of solvents containing water content <0.20% to give fosinoprilsodium polymorphic Form-A
 24. The process of claim 23 wherein in saidstep (d) (ix) the hydrolysis is effected by employing a base or an acidor a mixture of trichloromethyl silane and sodium iodide, with basepreferred.
 25. The process of claim 23, wherein in said step (d) (x),the base during esterification is selected from triethylamine, potassiumcarbonate, sodium carbonate and N-methyl morpholine.
 26. The process ofclaim 25, wherein said esterification in presence of base is carried outin a solvent selected from acetone and acetonitrile.
 27. The process ofclaim 23, wherein in said step (d) (x), the acid during esterificationis selected from sulphuric acid and p-toluene sulfonic acid.
 28. Theprocess of claim 27, wherein the esterification in presence of acid iscarried out in presence of a solvent selected from benzene, cyclohexaneand toluene, with cyclohexane preferred.
 29. The process of claim 23,wherein the solvent in step (d) (xi) is selected from acetonitrile,dichloroethane, dichloroethane, ethyl acetate, N,N-dimethyl acetamide,N,N-dimethyl formamide, tetrahydrofuran, toluene and xylene, with ethylacetate, toluene and xylene preferred.
 30. The process of claim 23,wherein in said step (d) (xi), compound (VI), wherein R⁷ is hydrogen isemployed in a molar ratio to compound (VII) of within the range of about1:4, preferably from about 1:1.5 to about 1:2.
 31. The process of claim23, wherein in said step (d)(xi), the base is selected fromtriethylamine, pyridine, tripropylamine, diazabicycloundecene andN-methylmorpholine.
 32. The process of claim 31, wherein the base isemployed in a molar ratio to compound (VI), wherein R⁷ is hydrogen ofwithin the range of about 1:4, preferably from about 1:1.5 to about 1:2.33. The process of claim 23, wherein in said step (d) (xii), the solventis selected from the group consisting of one or more of acetonitrile,ethanol, ethyl acetate, methanol, N,N-dimethyl acetamide, N,N-dimethylformamide, tetrahydrofuran, toluene and xylene, with dichloromethane,ethyl acetate, toluene and xylene preferred.
 34. The process of claim23, wherein in said step (d) (xiii), the cesium metal carrier isselected from cesium carbonate, cesium bicarbonate and cesium ethylhexanoate.
 35. The process of claim 34, wherein the cesium metal carrieris employed in a molar ratio to compound (II A)/(II B)/(II C)/(II D) ofwithin the range of about 1:3, preferably from about 1:1.5.
 36. Theprocess of claim 23, wherein in said step (d) (xiii), the solvent isselected from one or more of acetone, acetonitrile, dichloromethane,dichloroethane, diethyl ether, diisopropyl ether, dioxane, ethylacetate, methyl ethyl ketone, methyl isobutyl ketone, N,N-dimethylacetamide, N,N-dimethyl formamide, tertiary butyl methyl ether,tetrahydrofuran, toluene and xylene or mixtures thereof.
 37. The processof claim 23, wherein in said step (d) (xiii), the water content in thesolvent during crystallisation of compound (III A) is in a molar ratioof 1:10 to compound (II A)/(II B)/(II C)/(II D), preferably of withinthe range of about 1:5.
 38. The process of claim 23, wherein in saidstep (d) (xiv), the acid is selected from hydrochloric acid, nitricacid, sulphuric acid and potassium hydrogen sulfate, with potassiumhydrogen sulfate preferred.
 39. The process of claim 23, wherein in saidstep (d) (xiv), the solvent is selected from dichloromethane,dichloroethane, diethyl ether, diisopropyl ether, ethyl acetate, methylethyl ketone, methyl isobutyl ketone, N,N-dimethyl acetamide,N,N-dimethyl formamide, tetrahydrofuran, toluene and xylene.
 40. Theprocess of claim 23, wherein in said step (e) (xv), the sodium metalcarrier is selected from sodium acetate, sodium carbonate, sodiumbicarbonate and sodium ethyl hexanoate.
 41. The process of claim 23,wherein in said step (e) (xv), the solvent is selected from one or moreof acetonitrile, dichloromethane, dichloroethane, diethyl ether,diisopropyl ether, dioxane, ethyl acetate, methyl ethyl ketone, methylisobutyl ketone, N,N-dimethyl acetamide, N,N-dimethyl formamide,tetrahydrofuran, toluene and xylene, with dichloromethane and ethylacetate preferred.
 42. The process of claim 23, wherein in said step (e)(xvi), the water content of the total solvents is within the range fromabout 0.03 to 0.05%. 43-53. (canceled)